sildenafil-citrate and Metabolic-Syndrome

In the past decade, impressive strides have been made in the diagnosis and management of atherosclerotic, aneurysmal, and thromboembolic diseases, thanks in large part to the explosive growth in both vascular biology and clinical vascular medicine. We review what we consider to be the top 12 advances in this field: the discovery of nitric oxide, the metabolic syndrome, new thrombophilic disorders, therapeutic angiogenesis, endoluminal treatment of chronic venous disease, and a variety of drugs, including sildenafil, cilostazol, low-molecular-weight heparins, oral direct thrombin inhibitors, clopidogrel, statins, and angiotensin-converting enzyme inhibitors and angiotensin-receptor blocking agents.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cilostazol; Clopidogrel; Factor V; Heparin, Low-Molecular-Weight; Hot Temperature; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metabolic Syndrome; Mutation; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Purines; Sildenafil Citrate; Sulfones; Tetrazoles; Thrombin; Ticlopidine; Vascular Diseases; Vascular Surgical Procedures

The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction.. To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil.. IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2).. Two-center study.. Obese AA women.. A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks.. IS, FMD.. G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], -0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, -0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, -2.6 (95% CI, -5.1 to -0.1; P = .04).. The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.

Topics: Adult; Cardiovascular Diseases; Case-Control Studies; CD36 Antigens; Drug Resistance; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Humans; Insulin Resistance; Metabolic Syndrome; Middle Aged; Obesity; Phosphodiesterase 5 Inhibitors; Polymorphism, Single Nucleotide; Sildenafil Citrate; Treatment Outcome; Vasodilation

Diabetic erectile dysfunction (DMED) refers to erectile dysfunction secondary to diabetes. Erectile dysfunction is characterized by a persistent inability to achieve and maintain an erection sufficient to permit satisfactory sexual activity.. Based on the Web of Science core collection database, we firstly analyzed the quantity and quality of publications in the field of DMED, secondly profiled the publishing groups in terms of country, institution, author's publication and cooperation network, and finally sorted out and summarized the hot topics of research.. From 2001 to 2022, a total of 1,403 articles relating to this topic were published in 359 journals. They represent the global research status, potential hotspots, and future research directions. The number of DMED-related publications and citations has steadily increased over the few past decades. Academic institutions from Europe and the United States have played a leading role in DMED research. The country, institution, journal, and author with the most publications were the United States (294), INHA University (39), the Journal of Sexual Medicine (156), and Ryu, Ji-Kan (29), respectively. The most common keywords were erectile dysfunction (796), men (256), diabetes (254), diabetes mellitus (239), prevalence (180), corpus cavernosum (171), dysfunction (155), mellitus (154), nitric-oxide synthase (153), and expression (140). The main keyword-based research topics and hotspots in the DMED field were oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis.. The terms oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis will be at the forefront of DMED-related research.

Topics: Animals; Bibliometrics; Diabetes Mellitus, Experimental; Erectile Dysfunction; Humans; Male; Metabolic Syndrome; Rats; Rats, Sprague-Dawley; Sildenafil Citrate

Although decreased protein kinase G (PKG) activity was proposed as potential therapeutic target in heart failure with preserved ejection fraction (HFpEF), randomized clinical trials (RCTs) with type-5 phosphodiesterase inhibitors (PDE5i) showed neutral results. Whether specific subgroups of HFpEF patients may benefit from PDE5i remains to be defined. Our aim was to test chronic sildenafil therapy in the young male ZSF1 obese rat model of HFpEF with severe hypertension and metabolic syndrome. Sixteen-week-old ZSF1 obese rats were randomly assigned to receive sildenafil 100 mg·Kg

Topics: Animals; Glucose Tolerance Test; Heart; Heart Failure; Male; Metabolic Syndrome; Obesity; Rats; Rats, Inbred WKY; Sildenafil Citrate; Stroke Volume; Vasodilator Agents

Much evidence indicates that metabolic syndrome is strongly correlated with a decrease in nitric oxide and an increase in oxidative stress leading to cardiovascular alterations. In recent years, gut microbiota has emerged as a new contributor to the metabolic syndrome establishment and associated cardiovascular diseases, but the underlying mechanisms remain unclear. We hypothesized that a positive modulation of cyclic guanosine monophosphate (cGMP) pathway, through phosphodiesterase type 5 (PDE5) inhibition could prevent cardiovascular alterations and gut dysbiosis that may be associated to metabolic syndrome. Spontaneously hypertensive rats (SHR) were randomly divided into 4 groups: control, cafeteria diet (CD) and sildenafil citrate treated groups (5mg/kg per os) were given either a CD or a standard chow diet for 10 weeks. Body weight, arterial blood pressure and glucose tolerance test were monitored. At the 10th week, cardiac inotropy and coronary perfusion pressure were evaluated on isolated heart according to Langendorff method. Cumulative concentration response curves to phenylephrine and acetylcholine were determined on thoracic aorta rings for vascular reactivity evaluation. Faecal samples were collected for the gut microbiota analysis. Compared to the control group, CD-fed rats showed a significant increase in body weight gain, arterial blood pressure and were glucose intolerant. This group showed also a decrease in β-adrenoceptor-induced cardiac inotropy and coronary vasodilation. Gut microbiota analysis revealed a significant reduction in the abundance of Lactobocillus spp in cafeteria diet-fed rats when compared to the control ones. Sildenafil citrate long-term treatment decreased weight gain and arterial blood pressure, improved coronary vasodilation and reduced α1-adrenoceptor-induced vasoconstriction in CD group. However, it did not reverse gut dysbiosis induced by chronic CD feeding. These results suggest that cGMP pathway targeting may be a potential therapeutic strategy for the management of the metabolic syndrome and associated cardiovascular disorders.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Blood Pressure; Cardiovascular Diseases; Cyclic GMP; Diet; Disease Models, Animal; Gastrointestinal Microbiome; Glucose Tolerance Test; Male; Metabolic Syndrome; Phenylephrine; Phosphodiesterase 5 Inhibitors; Rats; Rats, Inbred SHR; Sildenafil Citrate; Vasodilation; Vasodilator Agents

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and decreased nitric oxide bioactivity in cavernosal tissue. The role of nitric oxide on erectile function is well known. Statins have lipid lowering properties and can modulate endothelial nitric oxide bioavailability. Sildenafil, enhances smooth muscle relaxation in corpus cavernosum. We investigated in-vitro effects of sildenafil and rosuvastatin on nonadrenergic, non-cholinergic and nitric oxide mediated cavernosal smooth muscle relaxation in metabolic syndrome rabbits, since alterations in this pathway are recognised in diabetic and hypercholesterolemic erectile dysfunction.. Ten male rabbits were fed a standard diet as control group, fourty male rabbits were fed a hypercholesterolemic diet for 12 weeks. Hypercholesterolemic group were divided for without treatment, rosuvastatin treatment, sildenafil treatment, and rosuvastatin + sildenafil treatment (N = 10 per groups).. Serum levels of cholesterol and glucose were significantly higher in the experimental group than in the control group (p < 0.05). After therapy no differences were found among the groups in relaxation responses to sodium nitroprusside. The relaxation responses to carbachol and EFS were significantly reduced in metabolic syndrome group to control group (p < 0.05), but there were no differences between the other groups and control group. There was a significantly lower in-vitro relaxation response in the metabolic syndrome rabbits than in controls and the others (p < 0.05).. Both agents improve in-vitro relaxation responses of erectile tissue from metabolic syndrome rabbits to endothelial non-adrenergic, non-cholinergic and nitric oxide. This finding supports to the results of other clinical studies with these drugs.

Topics: Animals; Disease Models, Animal; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Male; Metabolic Syndrome; Muscle Contraction; Muscle Relaxation; Myocytes, Smooth Muscle; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrimidines; Rabbits; Rosuvastatin Calcium; Sildenafil Citrate; Sulfonamides; Sulfones

Insulin resistance features both endothelial dysfunction and increased oxidative stress. Both disorders are targeted by a chronic treatment with sildenafil. However, the mechanism of action by which chronic sildenafil exerts its effects on reactive oxygen species sources is still largely unknown.. We therefore investigated how chronic sildenafil administration could impact vascular endothelial NO and superoxide release in a rat model of insulin resistance induced by fructose overload.. Adult male Wistar rats were fed a fructose-enriched diet (fructose-fed rats [FFR]) for 9 weeks. From weeks 6-8, sildenafil was administered subcutaneously twice daily (20 mg/kg), followed by a 1-week washout.. Vascular endothelial NO and superoxide release were monitored in vitro in thoracic aortic segments using oxidative fluorescence. Specific inhibitors were used to distinguish the respective role of the main superoxide-producing systems within the vascular wall (i.e., mitochondrial respiratory chain and NADPH oxidases). The levels of expression of eNOS, Akt, and NADPH oxidase subunits were determined in the abdominal aorta.. Chronic sildenafil administration corrected hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in FFR. Moreover, after 9 weeks of diet, while global unstimulated aortic endothelial NO and superoxide release were unchanged in FFR, the relative contribution of the mitochondrial respiratory chain and NADPH oxidases was modified. Chronic sildenafil treatment, even after the 1-week washout period, was able to increase endothelial NO release independently of Akt-dependent phosphorylation by up-regulating eNOS expression, and restored the relative contribution of each superoxide-producing system examined, yielding endothelial superoxide release. Finally, in vitro incubation of aortic segments with sildenafil markedly decreased the endothelial aortic superoxide release.. The present study showed that chronic sildenafil produced sustained vascular antioxidant effects in insulin-resistant rats by increasing NO release and regulating vascular superoxide release, supporting therefore further investigations using chronic sildenafil administration in preventing cardiovascular alterations associated with oxidative stress.

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Drug Administration Schedule; Endothelium, Vascular; Injections, Subcutaneous; Insulin Resistance; Male; Metabolic Syndrome; Nitric Oxide; Oxidative Stress; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Superoxides; Vasodilator Agents

Metabolic syndrome (MetS) is a clustering of cardio-metabolic risk factors (hyperglycemia, hypertension, dyslipidemia, visceral fat accumulation) that is also associated with hypogonadism and erectile dysfunction (ED).. To clarify the relationships among MetS, hypogonadism, and ED, we developed an animal model of MetS.. Male rabbits fed a high-fat diet (HFD), with or without testosterone (T) supplementation, were compared with control rabbits (fed a standard chow) and with rabbits made hypogonadal by a single injection of a long-acting GnRH-analog, triptorelin.. Evaluation of metabolic disturbances (plasma glucose, cholesterol, triglycerides, testosterone, LH, FSH level, glucose tolerance, mean arterial pressure, visceral fat accumulation), and corpora cavernosa (CC) relaxant capacity (in vitro contractility study) in HFD animals as compared with control, GnRH analog-treated rabbits, and T-supplemented HFD rabbits.. HFD rabbits showed all the features of MetS. HFD induced hypogonadotropic hypogonadism is characterized by a reduction of plasma T, FSH, LH levels, testis and seminal vesicles weight, and testicular steroidogenic enzymes. Such a phenotype is similar to that induced by triptorelin administration. A reduced GnRH immunopositivity in hypothalamus suggests a central origin of HFD-related hypogonadism. HFD also induced penile alterations, as demonstrated by a reduction of acetylcholine-and electrical field stimulation-induced CC relaxation, hyper-responsiveness to the NO donor, SNP, and unresponsiveness to PDE5 inhibitors. Similar penile alterations were observed in triptorelin treated rabbit. In HFD, as well as in triptorelin treated rabbits, PDE5 and eNOS mRNA expression quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) were significantly decreased. T administration prevented almost all penile alterations observed in HFD rabbits. T treatment dramatically reduced HFD-induced visceral obesity, partially ameliorating also the metabolic profile.. We have developed an animal model of MetS associated with hypogonadotropic hypogonadism and penile alterations including unresponsiveness to PDE5 inhibitors. T supplementation was able to partially revert HFD-induced phenotype.

Topics: Animals; Blood Glucose; Disease Models, Animal; Drug Synergism; Erectile Dysfunction; Glucose Tolerance Test; Hypogonadism; Male; Metabolic Syndrome; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Rabbits; Sildenafil Citrate; Sulfones; Testosterone

Several recent studies suggested that the prevalence of erectile dysfunction (ED) was higher in men with metabolic syndrome (MS).. We analyzed the impact of MS on the responsiveness to sildenafil.. A total of 133 ED patients were evaluated for the prevalence of MS and graded on severity of ED. MS was diagnosed according to the International Diabetes Federation (IDF) definition. The severity of ED was evaluated by the International Index of Erectile Function (IIEF) questionnaire. Hormonal parameters were measured for all patients, and the IIEF questionnaire was conducted after administration of eight tablets of 50-mg doses of sildenafil. If the scores to questions 3 and 4 of the IIEF were 4 or higher after administration, the patients were defined as responders to sildenafil.. To clarify the negative impact of MS on the responsiveness to sildenafil.. The mean age of the patients was 56.9 years, and 25 patients were diagnosed with MS. The IIEF-erectile function score and the response rate for sildenafil decreased as the number of MS components increased. Logistic regression analysis showed that the presence of MS along with severity of ED and history of pelvic surgery were significant independent risk factors of nonresponse for sildenafil. The hazard ratio for the presence of MS was 3.30 (95% confidence interval [CI]: 1.17-9.73). No meaningful association was observed between total testosterone or free testosterone levels and MS in this population.. We demonstrated the negative impact of MS on the responsiveness to sildenafil. Erectile function and response rate for sildenafil decreased as the number of MS components increased.

Topics: Drug Resistance; Erectile Dysfunction; Humans; Japan; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Phosphodiesterase Inhibitors; Piperazines; Prostatectomy; Purines; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Sulfones